We have demonstrated that highly active antiretroviral therapy based structured treatment interruptions (STI-HAART) can boost SIV-specific immune responses, thereby reducing the viral rebound rate and inducing immune control of SIV in acutely SIV251-infected macaques. However, during chronic infection, characterized by impaired immune functions, STI-HAART does not induce immune control. To reconstitute virus-specific immunity we have developed a novel topical therapeutic DNA vaccine, called DermaVir. Application of DermaVir to the surface of the skin of mice and macaques resulted in transduction of Langerhans cells, migration of these cells into lymph nodes, gene expression by genetically-modified dendritic cells, and induction of vigorous, virus-specific T cell-mediated immune responses. In chronically SIV251-infected macaques and in macaques with late-stage disease, i.e. AIDS, DermaVir, in combination with STI-HAART, reduced viral rebound to a rate comparable to that observed during STI-HAART alone during primary infection. These unexpected and exciting initial results warrant further investigation of the effects of DermaVir on immune control of HIV. We propose to evaluate various aspects of this novel therapeutic modality in the same SIV251-infected macaque model to create the basis for moving to the clinical stage of development. This project will run a comparative study to evaluate the importance of a two major factors that may increase both efficacy and safety of therapeutic immunization: type of promoter (LTR or CMV), and the use of an adjuvant, such as IL-2. Additionally, we propose to study the virus-specific humoral and cellular immune responses to DermaVir during the proposed primate trials in order to establish immune correlates of virus control. Specific Aim 1. Comparative analysis of the DNA promoter and potential adjuvants during DermaVir therapeutic immunization in non-human primates. To run a comparative study of the type of promoter (LTR or CMV) and the effects of an adjuvant (IL-2) on therapeutic immunization in a non-human primate model. Specific Aim 2. Study of immune correlates of viral control during therapeutic immunization. To determine whether the immune response elicited by DermaVir is responsible for the control of viremia, and to elucidate the nature of such a response.